Kate D. Williamson

Performance of the Glasgow-Blatchford score in predicting clinical outcomes and intervention in hospitalized patients with upper GI bleeding

BACKGROUND Data regarding the utility of the Glasgow-Blatchford bleeding score (GBS) in hospitalized patients with upper GI hemorrhage are limited. OBJECTIVE To evaluate the performance of the GBS in predicting clinical outcomes and the need for interventions in patients with upper GI hemorrhage. DESIGN Prospective observational study. SETTING Single, tertiary-care endoscopic center. PATIENTS Between July 2010 and July 2012, 888 consecutive hospitalized patients managed for upper GI hemorrhage were entered into the study. INTERVENTION GBS and Rockall scores. MAIN OUTCOME MEASUREMENTS GBS and Rockall scores were prospectively calculated. The performance of these scores to predict the need for interventions and outcomes was assessed by using a receiver operating characteristic curve. RESULTS Endoscopy was performed in 708 patients (80%). A total of 286 patients (40.3%) required endoscopic therapy, and 29 patients (3.8%) underwent surgery. GBS and post-endoscopy Rockall scores (post-E RS) were superior to pre-endoscopy Rockall scores in predicting the need for endoscopic therapy (area under the curve [AUC] 0.76 vs 0.76 vs 0.66, respectively) and rebleeding (AUC 0.71 vs 0.64 vs 0.57). The GBS was superior to Rockall scores in predicting the need for blood transfusion (AUC 0.81 vs 0.70 vs 0.68) and surgery (AUC 0.71 vs 0.64 vs 0.51). Patients with GBS scores ≤ 3 did not require intervention. LIMITATIONS Subjective decision making as to need for endoscopic therapy and blood transfusion. CONCLUSION Compared with post-E RS, the GBS was superior in predicting the need for blood transfusion and surgery in hospitalized patients with upper GI hemorrhage and was equivalent in predicting the need for endoscopic therapy, rebleeding, and death. There are potential cutoff GBS scores that allow risk stratification for upper GI hemorrhage, which warrant further evaluation.

New Therapeutic Strategies for Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, which in the majority of patients progresses to liver transplantation or death. To date, no medical treatment has been proven to be of benefit, although ursodeoxycholic acid is widely used. The etiopathogenesis of PSC is unclear, although it is associated with inflammatory bowel disease. Various hypotheses have been suggested, which have led to different therapeutic strategies. Recent studies have suggested that the microbiome may play a role in PSC, raising the possibility of efficacy of antibiotics and fecal microbiota transplantation. Gut-homing T cells may be important in the pathogenesis of PSC, and several agents are in development, targeting various receptors, integrins, and ligands on this pathway, including VAP-1, MAdCAM-1, α4β7, and CCR9. Nuclear receptor agonists such as obeticholic acid and fibrates hold promise, as do other therapies that alter bile acid composition such as norUDCA. Antifibrotic agents such as Loxl2 inhibitors are also being assessed. In conclusion, it is likely that an effective drug therapy for PSC will become available over the next decade.

Editorial: further evidence for the role of serum alkaline phosphatase as a useful surrogate marker of prognosis in PSC

In recent years, anti-tumour necrosis factor (TNF) drugs have been added to the medical armamentarium for patients with chronic active ulcerative colitis (UC). For those to whom these drugs are available, this has provided an important nonsurgical option. There are limited data about the success of adalimumab (ADA) to induce response after previous infliximab treatment. This study answers this important question and furthermore identifies factors which predict response. All patients in the study (n = 73) had previous exposure to IFX, early ADA levels available, and ≥1 year follow-up after commencing ADA therapy. Short-term response was defined as an improvement in the partial Mayo score at week 12, with long-term response defined as continued treatment with ADA, without the need for corticosteroids by week 52. Overall response rates were 75% and 52% at weeks 12 and 52, respectively. Nonresponders to IFX were less likely to respond to ADA than those who stopped IFX for other reasons. Response was also predicted by higher early ADA levels, with levels >4.5 lg/mL at 4 weeks predicting 12-week response, and levels >7 lg/mL at 4 weeks predicting 52-week response. The key message from this study is that nonresponse, loss of response or drug reaction to IFX does not denote a class effect necessitating abandonment of anti-TNF, and that ADA is a good second-line treatment in such patients. The prognostic value of performing anti-TNF drug and anti-drug antibody testing is also demonstrated, and this could hold the key to the improved patient selection which might alter the cost to benefit ratio for this class of therapies.

Clinical triage for colonoscopy is useful in young women.

BACKGROUND Colonoscopy is an invasive procedure and a limited resource. It is therefore desirable to restrict its use to those in whom it yields an important diagnosis, without missing pathology in others. AIM The aim of this study was to determine whether standard clinical criteria can be used to reliably distinguish when colonoscopy is advisable in women 30 years and younger. METHODS A retrospective audit was performed at a single centre of 100 consecutive colonoscopies performed in women 30 years old and younger. The indications for the colonoscopy were recorded, and divided into clear and relative indications. The primary outcome of whether an endoscopic diagnosis was made was compared between the two groups. Clear indications for colonoscopy included overt rectal bleeding, elevated inflammatory markers, anaemia, iron deficiency and strong family history of colorectal cancer. Relative indications included abdominal pain or discomfort, bloating and altered bowel habit/motions. RESULTS The average age was 23 years. Sixty women had both relative and clear indications. Eleven had only clear indications and 28 only relative indications. Altogether, 58 colonoscopies were normal, and 17 showed inflammatory bowel disease. No subject with only relative indications had an abnormal finding (0/28). The diagnostic yield was significantly different between those with only relative indications (0%) versus those with at least one clear indication (59%; P < 0.0001). CONCLUSIONS Standard clinical criteria can be used to restrict safely the use of colonoscopy in young women. This will avoid performing procedures in people without clear indications, saving costs, resources and complications.

A novel prognostic model for transplant-free survival in primary sclerosing cholangitis

Objective Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables. Design The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models’ predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates. Results The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up. Conclusion The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available.

A Large Shin Ulcer After Minor Trauma: Please Do Not Debride!

Question: A 21-year-old, obese man presented with a large right shin ulcer after a gentle knock against cement steps 2 weeks earlier (Figure A). He was diagnosed with left-sided ulcerative colitis 6 months prior and was managed successfully with azathioprine (200 mg/d) and balsalazide (2.25 g TDS). His colitis, however, relapsed 3 weeks before this presentation, related to noncompliance with medication. This was treated with high-dose prednisolone (50 mg/d). He described that the related “bruise” from the gentle knock developed into a small pustule over a period of 5 days, which subsequently burst, ulcerated, and was exquisitely painful. The ulcer was initially managed at a country hospital with surgical debridement and antibiotics that, paradoxically, increased ulcer size rapidly. On arrival to our tertiary institution, he was unwell with a fever (37.9°C) and a large (12 12 cm) raised violaceous border, nfected, right pretibial necrotic-based ulcer. His bloody diarrhea had resolved and his abdomen was soft and nontender. Initial aboratory investigations revealed elevated C-reactive protein (85 mg/L; RR 8), neutrophilia (absolute neutrophil count, 9.50 09/L), and mild anemia (hemoglobin,118g/L). Mild to moderately severe pancolitis was seen at colonoscopy (Figure B). Biopsies ere taken from the ulcer at initial surgical debridement (Figure C). Two weeks of intravenous meropenem was given for Staphylococcus aureus wound infection and Burkholderia cepacia bacteremia. Despite the addition of prednisolone (100 mg/d), cyclosporine (500 mg/d), betamethasone ointment, and silver sulfadiazine dressings, the ulcer did not improve. Only after infliximab therapy (5 mg/kg) did his ulcer improve and reduce to 7.5 cm after 2 months (Figure D). What is the diagnosis? What are the management options for this condition? See the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

Inpatient Health Care Utilisation in patients with Alcoholic Liver Disease: What are the costs and outcomes?

Alcoholic liver disease (ALD) carries a significant cost burden and often leads to inpatient care. It is unclear whether inpatient care for ALD is any more costly than admission for other reasons.

Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications: Biliary gene transporters in severe ICP

Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes.

Unique and Common Features of Innate-Like Human Vδ2+ γδT Cells and Mucosal-Associated Invariant T Cells

Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans that can be activated in a TCR-independent manner by inflammatory and antiviral cytokines. In humans, the capacity for TCR-independent activation is functionally linked to a transcriptional program that can be identified by the expression of the C-type lectin receptor, CD161. In addition to MAIT cells, it has been demonstrated that a subset of γδT cells expresses CD161 and can be activated by TCR-independent cytokine stimulation. In this study, we sought to clarify the nature of cytokine-responsive human γδT cells. We could link CD161 expression on Vδ2+ versus Vδ1+ γδT cells to the observation that Vδ2+ γδT cells, but not Vδ1+ γδT cells, robustly produced IFN-γ upon stimulation with a variety of cytokine combinations. Interestingly, both CD161+ and CD161− Vδ2+ γδT cells responded to these stimuli, with increased functionality within the CD161+ subset. This innate-like responsiveness corresponded to high expression of PLZF and IL-18Rα, analogous to MAIT cells. Vδ2+ γδT cells in human duodenum and liver maintained a CD161+ IL-18Rα+ phenotype and produced IFN-γ in response to IL-12 and IL-18 stimulation. In contrast to MAIT cells, we could not detect IL-17A production but observed higher steady-state expression of Granzyme B by Vδ2+ γδT cells. Finally, we investigated the frequency and functionality of γδT cells in the context of chronic hepatitis C virus infection, as MAIT cells are reduced in frequency in this disease. By contrast, Vδ2+ γδT cells were maintained in frequency and displayed unimpaired IFN-γ production in response to cytokine stimulation. In sum, human Vδ2+ γδT cells are a functionally distinct population of cytokine-responsive innate-like T cells that is abundant in blood and tissues with similarities to human MAIT cells.

Author reply: To PMID 25644364.

We thank Russell and Stevenson for their comments on our clinical audit published recently in the Internal Medicine Journal. Our retrospective clinical audit of 100 women under 30 years undergoing colonoscopy found that patients with only relative indications had a very low diagnostic yield (0% in our cohort) as compared with those with clear indications. We agree with the comments made that these data should be interpreted with caution due to the 95% confidence interval of making a diagnosis in a colonoscopy in this cohort for only a relative indication being 0–12%. However, even if we take the worst-case scenario with a yield of 12%, this is vastly different from the yield in those with a ‘clear’ indication (58%, 95% confidence interval 47–69%), a difference which is both statistically and clinically significant. Additionally, we believe that these data strongly support the American Society of Gastrointestinal Endoscopy (ASGE) guidelines, which indicate that colonoscopy should not be performed in patients with ‘chronic, stable, irritable bowel syndrome or chronic abdominal pain’. The ASGE does note that there are unusual exceptions in which colonoscopy may be performed once to rule out disease, especially if symptoms are unresponsive to therapy, and we point out that the use of faecal calprotectin may be advantageous here. Furthermore, we wish to point out that the ASGE also recommend colonoscopy in the setting of ‘clinically significant diarrhoea of unexplained origin’. It may be argued what ‘clinically significant’ represents; and indeed, this is somewhat subjective, but we would suggest that this represents the subsets of patients who either have evidence of malabsorption or objective markers of infiammation (e.g. anaemia, raised CRP and/or platelets, iron deficiency, hypoalbuminaemia, hypokalaemia and weight loss), or who have frequent (greater than four times/day) or nocturnal diarrhoea. Indeed, this represents only a small subset of patients. Russell and Stevenson point out that these findings should be prospectively validated in a blinded fashion in a large multi-centre cohort. In an ‘ideal’ world, this might be true; however, to design such a trial where endoscopists were to perform a colonoscopy blinded to the indication, and moreover, in many situations, where we do not feel colonoscopy is indeed indicated at all, would not be ethical or safe and indeed possibly not practically feasible, as indications guide what biopsies to take, whether to intubate the ileum, the degree of urgency for the colonoscopy in the setting of instability during the sedation/anaesthetic and as well as, of course, interpretation of findings. Hence, the best and only data to support these recommendations come from retrospective cohort reviews, and this is the first Australian data published to support this practice as recommended by the ASGE. Hence, in a resource-strapped health system, we stand by our conclusion that for women under 30 years of age, these data should encourage gastroenterologists to be confident in making a positive diagnosis of functional gastrointestinal disease on clinical grounds in the absence of alarm symptoms (or ‘clear indications’) and reserve colonoscopy for subjects in whom the medical need for the procedure is greater.